The oral administration of active substances in the zootechnical field is a problem which is not easy to solve, in particular as regards the possibility to ensure intestinal absorption of adequate doses of said substances, avoiding their massive degradation during passage through the digestive tract of the animal, especially in the case of ruminants.
The aspects of the physiology of the digestive tract of ruminants and of other so-called companion animals or productive livestock are disclosed in detail in many specialist monographs. Among these, some also review the problems linked to the oral administration of active ingredients in such animals, as well as the possible solutions in terms of formulation technology (Development and formulation of veterinary dosage forms 2nd Edition, G. E. Hardee, J. D. Baggot (Edts) Marcell Dekker, New York 1998; S. H. W. Wu, A. Papas, Rumen stable delivery systems, Advanced drug delivery reviews 28 (1997) 323-334). The active ingredients and the supplements of the animal's diet undergo, in the proximal tract of the digestive system, an enzymatic and chemical degradation before reaching the intestinal lumen, which is the site of absorption for said substances. In ruminants, this degradation is particularly substantial due to the presence, in the rumen, of a microflora which degrades effectively many of the substances which pass through the rumen. One must also consider the slowness with which said substances pass through the rumen. This causes only a small part of the active substances or food supplements to be absorbed by ruminants at the intestinal level, since almost 100% of these molecules is degraded by the microflora of the rumen. Therefore, to allow such substances to be absorbed in the intestine and apply their effectiveness, it is necessary to protect them against degradation at the rumen level. It is in fact known that for example a substance such as choline or its salts are capable of increasing milk production in bovines when they are administered directly at the post-rumen level (S. R. Haretewell et al., J. Dairi Sci. (2000) 83, 2097-2017 and K. N. Deulcher et al., J. Dairi Sci., (1998) 81, 238-242).
U.S. Pat. No. 4,533,557, granted to Nippon Soda Ltd, discloses the composition of food supplements for ruminants in the form of granules or tablets which contain a mixture of biologically active substances, chitosan and protective materials constituted by saturated or unsaturated aliphatic monocarboxylic acids, with a chain having 14 to 22 carbon atoms. The concept behind this invention consists in using hydrophobic substances to build a matrix which is capable of slowing the penetration of biological fluids inside it and consequently of causing a slower release of the substance. The aim is therefore to extend the substance release time by reducing the amount thereof released during rumen transit. Further, the presence of chitosan should provide specific protection against the rumen environment: the pH of the fluid contained in the rumen varies between 5 and 8; chitosan is scarcely soluble in this pH range, but dissolves instead in an acid pH (<5). Therefore, the presence of this type of polymer should give greater integrity to the matrix during rumen holding.
U.S. Pat. No. 5,190,775, granted to the Balchem Corporation, discloses the composition of particles or granules for oral administration having a relative density between 0.3 and 2 g/ml, which contain a bioactive substance which is encapsulated by means of a hydrophobic coating which is constituted preferably by hydrogenated vegetable oils coated on their surface with a layer of surfactant in order to prevent its floating within the rumen. In the specific case in which the bioactive substance is choline chloride, it is adsorbed on a vegetable substrate derived from cereals.
In another patent, granted to Morgan Manufacturing Co., Inc. (U.S. Pat. No. 5,496,571), a method is disclosed for manufacturing microcapsules which are intended for oral administration and are designed to protect choline chloride against degradation caused by rumen bacteria in order to increase the production of milk in ruminants. These microcapsules contain liquid compositions of choline chloride coated with an outer layer of lipid material selected among hydrogenated and non-hydrogenated animal fats or among hydrogenated vegetable oils.
A series of other patents claims methods and compositions which entail coating a core which contains a bioactive substance by way of materials which are capable of withstanding at least partly rumen degradation and of dissolving and/or degrading in the abomasus or in the distal part of the intestine of ruminants. Among these patents, mention can be made for example of U.S. Pat. No. 4,713,245, U.S. Pat. No. 3,541,204, and U.S. Pat. No. 4,876,097.
U.S. Pat. No. 4,832,967, granted to Rhone Poulenc Santé, claims a composition for feeding ruminants which is constituted by a core which contains the bioactive substance, coated by two protective layers. The first of said coatings is a polymeric substance which is capable of forming a film which is stable at pH >5 but is capable of releasing the bioactive substance at pH <3.5. The second coating is a hydrophobic substance.
The preparation of multilayer polymeric microspheres for controlled release of drugs, fertilizers, insecticides and chemical indicators is claimed by U.S. Pat. No. 5,912,017, granted to the Massachusetts Institute of Technology.
In US Patent Publication No. 2005/0019413, Ascor Chimici S.r.l. claims a composition in the form of particles which contain choline chloride administered in a rumen-protected form. The particles are constituted by a core which consists mainly of choline chloride in the form of crystalline powder, coated by a double protective layer: externally, a continuous layer of carnauba wax and internally a continuous layer of a hydrophobic substance such as hydrogenated soybean oil. Moreover, the core can contain additional substances acting as flow modifiers (silicate, aluminosilicates, zeolites, silica, pearlite) in amounts not exceeding 8% of the weight of the core, and/or acting as binding agents which have a barrier function against moisture (stearates) in an amount equal to 7% of the weight of the core.
In a second patent application (US Patent Publication No. 2006/0067984), the same Ascor Chimici S.r.l. claims the invention of compositions in the form of pellets for controlled release of physiologically active substances for zootechnical use. These compositions comprise: i) a core constituted by the physiologically active substance and by a matrix of carnauba wax and/or microcrystalline wax; ii) a first hydrophobic coating layer, which consists of a material which belongs to the category of fats, fatty acids, hydrogenated oils, fatty acid mono- or diglycerides, fatty acid esters or long-chain alcohols (12 to 22 carbon atoms), with a melting point between 40 and 74° C.; iii) a second coating layer over the first one, which is constituted by microcrystalline waxes, paraffin waxes, vegetable waxes and synthetic waxes with a melting point between 80 and 100° C.
One of the claims further specifies that the matrix that constitutes the core can also contain hydrophobic silicates.